Direct mapping of the spin-filtered surface bands of a three-dimensional quantum spin Hall insulator

Spin-polarized band structure of the three-dimensional quantum spin Hall insulator $\rm Bi_{1-x}Sb_{x}$ (x=0.12-0.13) was fully elucidated by spin-polarized angle-resolved photoemission spectroscopy using a high-yield spin polarimeter equipped with a high-resolution electron spectrometer. Between the two time-reversal-invariant points, $\bar{\varGamma}$ and $\bar{M}$, of the (111) surface Brillouin zone, a spin-up band ($\Sigma_3$ band) was found to cross the Fermi energy only once, providing unambiguous evidence for the strong topological insulator phase. The observed spin-polarized band dispersions determine the "mirror chirality" to be -1, which agrees with the theoretical prediction based on first-principles calculations

A Modular Approach to the Incompressibility of Block-Cipher-Based AEADs

Incompressibility is one of the most fundamental security goals in white-box cryptography. Given recent advances in the design of efficient and incompressible block ciphers such as SPACE, SPNbox and WhiteBlock, we demonstrate the feasibility of reducing incompressible AEAD modes to incompressible block ciphers. We first observe that several existing AEAD modes of operation, including CCM, GCM(-SIV), and OCB, would be all insecure against white-box adversaries even when used with an incompressble block cipher. This motivates us to revisit and formalize incompressibility-based security definitions for AEAD schemes and for block ciphers, so that we become able to design modes and reduce their security to that of the underlying ciphers. Our new security notion for AEAD, which we name whPRI, is an extension of the pseudo-random injection security in the black-box setting. Similar security notions are also defined for other cryptosystems such as privacy-only encryption schemes. We emphasize that whPRI ensures quite strong authenticity against white-box adversaries: existential unforgeability beyond leakage. This contrasts sharply with previous notions which have ensured either no authenticity or only universal unforgeability. For the underlying ciphers we introduce a new notion of whPRP, which extends that of PRP in the black-box setting. Interestingly, our incompressibility reductions follow from a variant of public indifferentiability. In particular, we show that a practical whPRI-secure AEAD mode can be built from a whPRP-secure block cipher: We present a SIV-like composition of the sponge construction (utilizing a block cipher as its underlying primitive) with the counter mode and prove that such a construction is (in the variant sense) public indifferentiable from a random injection. To instantiate such an AEAD scheme, we propose a 256-bit variant of SPACE, based on our conjecture that SPACE should be a whPRP-secure cipher

SOX11 contributes to the regulation of GDF5 in joint maintenance

Background: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. Results: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5’ UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. Conclusions: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis

Interferon-α/β and Anti-Fibroblast Growth Factor Receptor 1 Monoclonal Antibody Suppress Hepatic Cancer Cells In Vitro and In Vivo

Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC..Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/β is a promising approach to the treatment of HCC

インスリン テイコウセイ カラ ミタ sirolimus-eluting stent ト paclitaxel-eluting stent ノ ナイマク ゾウショク ノ ケントウ

(目的)虚血性心疾患の治療において経皮的冠動脈形成術は有用な治療であるが再狭窄が問題である.これに対し,近年薬剤溶出性ステント(Drug eluting stent:DES)が臨床応用され再狭窄は減少してきているが依然として認めている.現在数種類のDES が臨床使用されているが,病態によりどのDES を選択するか明確な指標はない.主に使用されているシロリムス溶出性ステント(sirolimus-eluting stent:SES)とパクリタキセル溶出性ステント(paclitaxel-eluting stent:PES)では塗布されている薬剤の作用機序が異なる.以前我々はDES 留置後においてもインスリン抵抗性が内膜増殖に関与していると報告してきた.本研究の目的は作用機序の異なるこれら2 つのDES において,内膜増殖とインスリン抵抗性の関与を比較検討することである.(方法)2007 年5 月から2009 年12 月までにPCI を施行しDES を留置した212 例をSES 留置例とPES 留置例それぞれで,インスリン抵抗性を認める群(P 群)と認めない群(N 群)に分けて再狭窄を検討した.(結果)再狭窄はSES 留置例,PES 留置例ともにP 群とN 群とで有意差を認めなかった.QCA 解析をするとPES 留置例では,最小血管径(minimum lumen diameter:MLD),%狭窄率(% stenosis),晩期損失径(late lumen loss)に有意差を認めなかったが,SES 留置例では最小血管径で2.18±0.77, 2.61±0.53(p=0.028),晩期損失径で0.36±0.56, 0.13±0.22 mm( p=0.048)と有意差を認め,%狭窄率では20.36±24.44,12.2±6.86(p=0.098)とP 群で狭窄率が高い傾向を認めた.(結語)PES 留置後は慢性期の内膜増殖にインスリン抵抗性の影響を受けないが,SES 留置後はインスリン抵抗性が内膜増殖に関与している.Percutaneous coronary intervention(PCI) has been widely adopted as an effective treatmentstrategy for patients with ischemic heart disease. However,the rate of coronary artery restenosis is still high. Drugelutingstent( DES) have been implanted in clinical practiceand reduced the incidence of restenosis. Nevertheless, restenosisof coronary artery still occurs in DES patients. Twotypes of DES, sirolimus-eluting stent:SES and paclitaxelelutingstent:PES are widely applied. Previously we reportedthat insulin resistance is one of the factors for stentrestenosis. The aim of this study is to investigate the diferenceof intimal hyperplasia in insulin resistant patients withthe two types of DES implantation.METHODS:We studied the 320 patients who underwentPCI to a new lesion using DES between May 2007 andDecember 2009.We divided these patients by presence ofinsulin resistance into Group P (positive:n=120) andGroup N( negative:n=92). Furthermore, we divided thesepatients into implantation of SES and PES. We measuredthe minimal lumen diameter( MLD) and late loss by quantitativecoronary angiography( QCA).RESULTS:In SES implantation Group and PES implantationGroup, the rate of restenosis was no difference betweenGroup P and Group N. In PES implantation Group,MLD and Late Loss had no difference. However in SES implantationGroup, MLD was significantly lower ( 2.18±0.77vs 2.61±0.53 mm, p<0.05) and Late Loss was significantlyhigher in Group P compared with Group N (0.36±0.56 vs0.13±0.22 mm, p<0.05).CONCLUSION:We suggest that in patients who wereimplanted the two types of DES, insulin resistance was relatedto intimal hyperplasia. Especially SES patients withpositive insulin resistance prone to show more intimal hyperplasia

Framingham Risk Score ト ドウミャク コウカ リスク ニ ツイテノ ケントウ

背景:冠動脈疾患において以前よりフラミンガムリスクスコア(Framingham Risk Score:FRS)は10 年以内の虚血性心疾患発症を予測することが知られている.また近年,冠動脈マルチスライスCT(MultisliceConputed Tomography:MSCT)により求められる冠動脈カルシウムスコア(Coronary Artery CalciumScore:CACS)や種々の炎症マーカーが冠動脈疾患予測因子として報告されている.目的:年齢,性別,総コレステロール値,High Density Lipoprotein Cholesterol (HDL-C)コレステロール値,収縮期血圧,喫煙の有無から簡易に求めることのできるFRS を算出し,FRS と冠動脈疾患各動脈硬化リスク因子について検討した.対象:2009 年6 月から2011 年9 月までに当院に虚血性心疾患精査目的に受診しMSCT および,冠動脈造影を施行した連続347 例(男性229 例,女性108 例)についてFRS を計測し15 以上の高リスク群(H 群)と15未満の低リスク群(L 群)に分類した.冠動脈造影における有病率と冠動脈疾患予測因子であるCT にて計測されるCACS,及び血液検査における炎症マーカーについて比較検討した.結果:対象はH 群149 例,L 群198 例に分けられた.冠動脈造影における冠動脈疾患有病率はH 群53.6%,L 群41.4%とH 群において有意に高値であった(P=0.023).CACS においてもH 群687.1±759.1,L 群489.8±725.6 とH 群において有意に高値であった(P=0.015).血液検査におけるマーカーにおいては高感度CRP(H 群 vs L 群:0.29±0.70 vs 0.17±0.29 mg/dl P=0.046)と酸化Low Density Lipoprotein Cholesterol(LDL)(H 群 vs L 群:110.2±47.0 vs 96.8±35.6 U/L P=0.007)において有意差を認めた.結語:FRS は簡便に計測でき,各種冠動脈疾患予測因子とも関連しており冠動脈疾患予測の一助となりうる可能性があると考えた.Background: The Framingham risk score (FRS) is widely used inclinical practice to identify subjects at high risk for developingischemic heart disease. However, FRS may not accuratelyidentify subjects at risk. Recently, coronary arterycalcium score (CACS) detected by multi-slice computedtomography (MSCT) and several atherosclerosis riskmarkers has been known to predict ischemic heart diseases.Subjects: The aim of this study is to clarify the relation betweenFRS and several coronary risk factors. We researched theclinical records of 347 patients who had been subjected toMSCT and coronary angiography( CAG) between Jun 2009and September 2011. We subdivided these patients by thevalue of FRS into a group H (n=149;FRS &#8805; 15) and agroup L( n=198;FRS<15), and examined the relationshipbetween FRS and the other coronary risk factors.Results: The prevalence of coronary heart disease by CAG wassignificantly higher in group H (53.6 %) than in group L(41.4%, p=0.023). CACS was significantly higher in groupH than in group L( 687.0±759.1 vs 489.8±725.6, p=0.015).In group H the level of high-sensitive CRP and MDL-LDLwere significantly higher than those in group L(0.29±0.70vs 0.17±0.29 p=0.046 and 110.18±47.0 vs 96.82±35.6 P=0.007).Conclusion: We suggest that the FRS is easy to calculate and usefulto predict ischemic heart disease compared with the othercoronary risk markers

インスリン テイコウセイ カラ ミタ ヤクザイ ヨウシュツセイ ステント リュウチ ゴ ノ late catch up ゲンショウ ニ ツイテノ ケントウ

目的:虚血性心疾患の危険因子としてメタボリックシンドロームが注目されているが,その背景にはインスリン抵抗性が存在している.一方,虚血性心疾患の治療において経皮的冠動脈形成術(percutaneouscoronary intervention:PCI)は有用な治療法であるが再狭窄が課題である.近年薬剤溶出性ステント(Drugelutingstent:DES)が臨床応用され再狭窄は減少しているものの,ステント血栓症や晩期再狭窄であるlatecatch up 現象などの慢性期における新たな課題が散見されている.今回我々はインスリン抵抗性とDES 留置患者の慢性期の心血管イベントの関連を調べるためにインスリン抵抗性をHomeostasis Model Assessment 指数(HOMA-IR)を用いて検討した.方法:2004 年8 月より2008 年11 月までにPCI を施行しDES を使用した109 例についてHOMA-IR を計測しインスリン抵抗性を認める群(P 群:n=63)と認めない群(N 群:n=46)にわけ慢性期における心血管イベントについて検討した.結果:観察期間は平均で5.48±1.30 年であった.心臓死,再狭窄,心筋梗塞,脳梗塞,心不全,ステント血栓症においては両群間において有意差を認めなかった.しかしlate catch up 現象においてはP 群12.7%とN 群2.2%と有意差を認めた(p=0.048).結論:インスリン抵抗性はDES 留置後のlate catch up 現象の予測因子であった.インスリン抵抗性を改善させることにより慢性期における心血管イベントのさらなる減少が期待される.PURPOSE:Percutaneous coronary intervention( PCI) isan effective treatment for patients with ischemic heart disease;especially, restenosis is suppressed after drug-elutingstent (DES) implantation. However, several problemsstill remain. Previously, we reported neo-intimal proliferationafter DES implantation that was associated with insulinresistance. The aim of this study was to clarify whether insulinresistance was associated with Major Adverse Cardiacand Cerebrovascular Events (MACCE) after DES implantation.METHODS:We researched the clinical records of 109patients who had been subjected to elective PCI and DESimplantation between May 2007 and December 2010. Wedistributed these patients by the value of homeostasis modelassessment of insulin resistance (HOMA-IR) into aGroup P (n=63;HOMA-IR &#8805; 2.5, positive) and a Group N(n=46;HOMA-IR<2.5, negative), and examined the relationshipbetween HOMA-IR and MACCE.RESULTS:The observation period was 5.48±1.30years. There were no differences between the two groupsin the occurrence of cardiac death, restenosis, stroke, acutemyocardial infarction, heart failure and stent thrombosis.But late catch-up phenomenon in group P was significantlyhigher than in group N (12.7 % vs 2.2 % p=0.042). The logisticanalysis showed that the only independent predictorof late catch-up phenomenon was insulin resistance (OR6.55;95 % CI 0.79-54.32, p=0.049).CONCLUSION:We suggest that insulin resistance is auseful predictor of late catch-up phenomenon;furthermore,improvement of insulin resistance may contribute toprevent late catch-up phenomenon after DES implantation

コウド インスリン テイコウセイ ジョウタイ ニ オケル ヤクザイ ヨウシュツセイ ステント リュウチ ゴ サイキョウサク ノ ヨソク インシ ノ ケントウ

目的:虚血性心疾患に対する経皮的冠動脈形成術(Percutaneous coronary intervention:PCI)は有用な治療法として確立されている.薬剤溶出性ステント(Drug-eluting stent:DES)により,大きな問題であった再狭窄は減少したが,完全には克服されていない.最近糖尿病の前段階としてインスリン抵抗性が注目されており,再狭窄に影響を及ぼすことが示唆されている.今回我々はHomeostasis Model Assessment 指数(HOMA-IR)を用いてインスリン抵抗性の程度とDES 留置後の再狭窄の関連を検討した.方法:2007 年5 月から2010 年10 月までに待機的にPCI を施行しDES を留置した248 例について,HOMAIRより高度インスリン抵抗性を有する群(H 群:n=75)と中等度インスリン抵抗性を有する群(M 群:n=64)およびインスリン抵抗性を有さない群(L 群:n=109)に分類し,定量的冠動脈造影を用いて再狭窄率および再狭窄関連因子について検討した.結果:再狭窄率はH 群で有意に高かった(p=0.0005).慢性期最小血管径はH 群で他の2 群と比較して有意に小さかった(H:1.62±1.02 mm,M:2.42±0.48 mm,L:2.17±0.70 mm, p=0.0086).さらに%狭窄率はH 群で他の2 群と比較して有意に大きく(H:40.1±34.7%,M::14.7±10.4%,L:22.7±21.6%, p=0.0092),晩期損失径もH 群で他の2 群と比較して有意に大きかった(H:0.87±0.90 mm,M:0.19±0.17 mm,L:0.41±0.62 mm, p=0.0097).結論:高度インスリン抵抗性は,DES 留置後再狭窄の危険因子となりえると考えられた.INTRODUCTION: Percutaneous coronary intervention (PCI) has beenwidely adopted as an effective treatment strategy for patientswith ischemic heart disease;especially, restenosis issuppressed after drug-eluting stent (DES) implantation.However, coronary artery restenosis after DES implantationstill appear now and then. The aim of this study was toclarify the factors associated with coronary artery restenosisafter DES implantation and evaluate the homeostasismodel assessment of insulin resistance (HOMA-IR) indexas a predictor of restenosis.METHODS: We reserched the clinical records of 248 patients who hadbeen subjected to elective PCI and DES implantation betweenMay 2007 and December 2010. We divided these patientsby the value of HOMA-IR into three groups(GroupH;HOMA-IR≧5 . 0 , Group M;2 . 5≦HOMA-IRHOMA-IR), and examined the relationshipbetween coronary artery restenosis and HOMA-IR.RESULTS: The rate of restenosis was significantly higher in GroupH (26.7 %) than in the other two groups (M;7.8 % andL;8.3%, p=0.0005 %). Follow up MLD was significantlylower in Group H (H;1.62±1.02 mm v.s. M;2.42±0.48 mm v.s. L;2.17±0.70 mm, p=0.0086). Furthermore, %stenosis and late lumen loss was significantly higher inGroup H (H;40.1±34.7%, M;14.7±10.4%, L;22.7±21.6%, p=0.0092, and H;0.87±0.9 mm v.s. M;0.19±0.17 mmv.s. L;0.41±0.62 mm, P=0.0097). Logistic analysis showedthat the only independent predictor of restenosis was HOMA-IR over 5.0( OR 2.87;p=0.004).CONCLUSION: The results suggested that severe insulin resistance wasa predictor of restenosis after drug-eluting stent implantation;furthermore, that improvement of insulin resistancemay contribute to prevent coronary restenosis after drugelutingstent implantation

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target